We will examine uptake, accumulation (binding) and efflux of drugs and ions in the lung to elucidate transport mechanisms in pulmonary endothelium. The primary objective is to define mechanisms for transfer by vascular endothelium and to determine the influence of pH, electrolytes and lung inflation and ventilation on these processes. Both in vitro and in vivo systems will be employed. Kinetics of uptake and efflux of selected agents will be examined in isolated perfused rabbit lungs and in intact dogs. Passage of materials from blood to lymph will be measured in the latter preparation. Our studies will focus upon drugs and chemicals which have either therapeutic value (antibiotics, corticosteroids, bronchodilators) or toxic effects (narcotics, antineoplastic agents) in the lung. We will determine what conditions (such as hypoxia, etc.) alter pulmonary uptake and metabolism of these drugs and thereby influence their subsequent toxicity or therapeutic effectiveness. Since movements of ions across pulmonary membranes can affect composition of bronchial mucous and periciliary fluids, we will examine the transport of Cl-, K7, Na plus and Ca plus plus by pulmonary endothelium. The influence of hypoxia, changes in pH and drugs on ion transport will be determined. Pulmonary endothelial cells in culture will be used to study permeability at the level of the cell membrane. Uptake of radiolabeled drugs and ions will be measured in endothelial cells from pulmonary arteries and veins of experimental animals. Uptake, binding and efflux will be compared in cells from arteries and veins, and the mechanisms of these processes will be determined by use of specific inhibitors, competitive binding, and variation of conditions as indicated above.